Glycosaminoglycan-Interacting Small Molecule (GISMO) as Alzheimer's Therapeutics ABSTRACT The aim of this project is to develop a novel, disease-modifying oral therapeutic agent for the treatment of Alzheimer's Disease. In the first phase of this project, we identified promising lead compounds via proprietary Glycosaminoglycan-Interacting Small Molecule (GISMO) drug discovery platform. GISMOs are based on a novel hypothesis for the cause of Alzheimer's Disease and provide a new therapeutic principle for the treatment of this devastating neurodegenerative disease. Alzheimer's Disease is associated with the pathological aggregation (i.e., amyloidosis) of amyloid-beta peptides (Abeta peptides). According to GISMO hypothesis, Abeta aggregation is necessary but not sufficient to cause Alzheimer's Disease. Rather, excessive accumulation and storage of a class of complex polysaccharides, glycosaminoglycans (GAGs), in the lysosomes of nerve cells is another essential component of the pathological process leading to Alzheimer's Disease. In our current work we show that GISMOs directly target heparan sulfate GAGs (HS-GAGs), inhibit Abeta42 binding to HS-GAGs, and have potent biological activity in at several assays relevant to amyloidosis in nerve cell cultures. Specifically, we identified GISMO lead compounds that inhibit uptake of Abeta by neuronal cells, and display potent neuroprotective properties against Abeta peptides, Abeta40 and Abeta42. This is the first report of Abeta/HS-GAG inhibitors (GISMOs) having potent neuroprotective properties against toxic Abeta peptides. In addition to reducing the toxic accumulation of amyloid aggregates inside nerve cells, GISMOs may also slow the progression of Alzheimer?s disease by inhibiting the spread of amyloid proteopathic seeds in brain tissue. The identified lead compounds conform to Lipinski rules and display selectivity and other drug-like properties. These results provide in vitro target validation as well as justification for further development of GISMO compounds as Alzheimer's Disease therapeutics. In Specific Aim 1, we will assess the lead compounds for their pharmacokinetic profiles, oral bioavailability, blood-brain-barrier penetration, and establish their maximum tolerated dose (MTD). In Specific Aim 2, we will test the two best lead compounds (selected from Aim 1) for their efficacy in two transgenic mouse models of AD. We will treat transgenic AD mice with two compounds at three doses for each compound and evaluate the effectiveness of treatment using standard tests for learning and memory, as well as biochemical, histopathological, and immunochemical methods. In Specific Aim 3, we will perform further preclinical testing of the selected development candidate. The successful completion of these studies will allow us to select a development candidate for preclinical development, towards an IND, and clinical trials.